6-chlorine-substituted imidazo[1,2-a]pyridine carboxamides and the use thereof as soluble guanylate cyclase stimulators

Abstract

The present application relates to novel 6-chloro-substituted imidazo[1,2-a]pyridine-3-carboxamides, to processes for preparation thereof, to the use thereof, alone or in combinations, for treatment and/or prophylaxis of diseases, and to the use thereof for production of medicaments for treatment and/or prophylaxis of diseases, especially for treatment and/or prophylaxis of cardiovascular disorders.

1 . Compound having the systematic name ent-N-(2-amino-3-fluoro-2-methylpropyl)-6-chloro-8-[(2,6-difluorobenzyl)oxy]-2-methylimidazo[1,2-a]pyridine-3-carboxamide (enantiomer B) and the structural formula 
       
         
           
           
               
               
           
         
         and the N-oxides, salts, solvates, salts of the N-oxides and solvates of the N-oxides and salts thereof. 
       
     
     
         2 . Compound having the systematic name ent-N-(2-amino-5,5,5-trifluoro-2-methylpentyl)-6-chloro-8-[(2,6-difluorobenzyl)oxy]-2-methyl imidazo[1,2-a]pyridine-3-carboxamide (enantiomer B) and the structural formula 
       
         
           
           
               
               
           
         
         and the N-oxides, salts, solvates, salts of the N-oxides and solvates of the N-oxides and salts thereof. 
       
     
     
         3 . Compound having the systematic name ent-N-(2-amino-5-fluoro-2-methylpentyl)-6-chloro-8-[(2,6-difluorobenzyl)oxy]-2-methylimidazo[1,2-a]pyridine-3-carboxamide (enantiomer A) and the structural formula 
       
         
           
           
               
               
           
         
         and the N-oxides, salts, solvates, salts of the N-oxides and solvates of the N-oxides and salts thereof. 
       
     
     
         4 . Compound having the systematic name ent-N-(2-amino-5-fluoro-2-methylpentyl)-6-chloro-8-[(2,6-difluorobenzyl)oxy]-2-methylimidazo[1,2-a]pyridine-3-carboxamide (enantiomer B) and the structural formula 
       
         
           
           
               
               
           
         
         and the N-oxides, salts, solvates, salts of the N-oxides and solvates of the N-oxides and salts thereof. 
       
     
     
         5 . Compound having the systematic name ent-N-(2-amino-4,4-difluoro-2-methylbutyl)-6-chloro-8-[(2,6-difluorobenzyl)oxy]-2-methylimidazo[1,2-a]pyridine-3-carboxamide (enantiomer A) and the structural formula 
       
         
           
           
               
               
           
         
         and the N-oxides, salts, solvates, salts of the N-oxides and solvates of the N-oxides and salts thereof. 
       
     
     
         6 . Compound having the systematic name ent-N-(2-amino-4,4-difluoro-2-methylbutyl)-6-chloro-8-[(2,6-difluorobenzyl)oxy]-2-methylimidazo[1,2-a]pyridine-3-carboxamide (enantiomer B) and the structural formula 
       
         
           
           
               
               
           
         
         and the N-oxides, salts, solvates, salts of the N-oxides and solvates of the N-oxides and salts thereof. 
       
     
     
         7 . Compound having the systematic name rac-N-(2-amino-4-fluoro-2-methylbutyl)-6-chloro-8-[(2,6-difluorobenzyl)oxy]-2-methylimidazo[1,2-a]pyridine-3-carboxamide (racemate) and the structural formula 
       
         
           
           
               
               
           
         
         and the N-oxides, salts, solvates, salts of the N-oxides and solvates of the N-oxides and salts thereof. 
       
     
     
         8 . Compound having the systematic name ent-N-(2-amino-4-fluoro-2-methylbutyl)-6-chloro-8-[(2,6-difluorobenzyl)oxy]-2-methylimidazo[1,2-a]pyridine-3-carboxamide (enantiomer A) and the structural formula 
       
         
           
           
               
               
           
         
         and the N-oxides, salts, solvates, salts of the N-oxides and solvates of the N-oxides and salts thereof. 
       
     
     
         9 . Compound having the systematic name ent-N-(2-amino-4-fluoro-2-methylbutyl)-6-chloro-8-[(2,6-difluorobenzyl)oxy]-2-methylimidazo[1,2-a]pyridine-3-carboxamide (enantiomer B) and the structural formula 
       
         
           
           
               
               
           
         
         and the N-oxides, salts, solvates, salts of the N-oxides and solvates of the N-oxides and salts thereof. 
       
     
     
         10 . Process for preparing the compound of  claim 1 , comprising:
 [A] reacting a compound of the formula (I)   
       
         
           
           
               
               
           
         
         in which 
         T 1  represents (C 1 -C 4 )-alkyl or benzyl, 
         in an inert solvent in the presence of a suitable base or acid to give a carboxylic acid of the formula (II) 
       
       
         
           
           
               
               
           
         
         and subsequently reacting the carboxylic acid of the formula (II) in an inert solvent under amide coupling conditions with an amine selected from the group consisting of 
       
       
         
           
           
               
               
           
         
         and the protective group optionally present is, optionally in the presence of a catalyst, removed hydrogenolytically, 
         and optionally converting the resulting compounds with the appropriate (i) solvents and/or (ii) acids or bases to the solvates, salts and/or solvates of the salts thereof. 
       
     
     
         11 . (canceled) 
     
     
         12 . (canceled) 
     
     
         13 . Medicament comprising a compound as defined in  claim 1  in combination with an inert, nontoxic, pharmaceutically suitable excipient. 
     
     
         14 . Medicament comprising a compound as defined in  claim 1  in combination with a further active compound selected from the group consisting of organic nitrates, NO donors, cGMP-PDE inhibitors, antithrombotic agents, hypotensive agents and lipid metabolism modifiers. 
     
     
         15 . (canceled) 
     
     
         16 . Method for the treatment and/or prophylaxis of heart failure, angina pectoris, hypertension, pulmonary hypertension, ischaemias, vascular disorders, renal insufficiency, thromboembolic disorders and arteriosclerosis comprising administering an effective amount of at least one compound as defined in  claim 1  to a human or animal in need thereof. 
     
     
         17 . Method for treatment and/or prophylaxis of heart failure, angina pectoris, hypertension, pulmonary hypertension, ischaemias, vascular disorders, renal insufficiency, thromboembolic disorders and arteriosclerosis comprising administering an effective amount of the compound of  claim 2  to a human or animal in need thereof. 
     
     
         18 . Method for treatment and/or prophylaxis of heart failure, angina pectoris, hypertension, pulmonary hypertension, ischaemias, vascular disorders, renal insufficiency, thromboembolic disorders and arteriosclerosis comprising administering an effective amount of the compound of  claim 3  to a human or animal in need thereof. 
     
     
         19 . Method for treatment and/or prophylaxis of heart failure, angina pectoris, hypertension, pulmonary hypertension, ischaemias, vascular disorders, renal insufficiency, thromboembolic disorders and arteriosclerosis comprising administering an effective amount of the compound of  claim 4  to a human or animal in need thereof. 
     
     
         20 . Method for treatment and/or prophylaxis of heart failure, angina pectoris, hypertension, pulmonary hypertension, ischaemias, vascular disorders, renal insufficiency, thromboembolic disorders and arteriosclerosis comprising administering an effective amount of the compound of  claim 5  to a human or animal in need thereof. 
     
     
         21 . Method for treatment and/or prophylaxis of heart failure, angina pectoris, hypertension, pulmonary hypertension, ischaemias, vascular disorders, renal insufficiency, thromboembolic disorders and arteriosclerosis comprising administering an effective amount of the compound of  claim 6  to a human or animal in need thereof. 
     
     
         22 . Method for treatment and/or prophylaxis of heart failure, angina pectoris, hypertension, pulmonary hypertension, ischaemias, vascular disorders, renal insufficiency, thromboembolic disorders and arteriosclerosis comprising administering an effective amount of the compound of  claim 7  to a human or animal in need thereof. 
     
     
         23 . Method for treatment and/or prophylaxis of heart failure, angina pectoris, hypertension, pulmonary hypertension, ischaemias, vascular disorders, renal insufficiency, thromboembolic disorders and arteriosclerosis comprising administering an effective amount of the compound of  claim 8  to a human or animal in need thereof.